Current genetic medicines are limited by tolerability, scalability, and immunogenicity issues. Utilizing components from viral and non-viral delivery platforms, we developed a lipid-based delivery vehicle formulated with a chimeric fusion protein that delivers nucleic acid cargo inside cells effectively and with broad distribution and low immunogenicity. This proteolipid vehicle platform is suitable for safe and effective repeat dosing of DNA and/or RNA in vivo.
Researchers at the University of Geneva, together with colleagues in Switzerland, France, the United States and Israel, describe how optogenetic control of brain cells and circuits is already steering both indirect neuromodulatory therapies and first-in-human retinal interventions for blindness, while sketching the practical and ethical conditions needed for wider clinical use.
Optogenetic control uses light to impose temporally precise gain or loss of function in specific cell types, or even individual cells. Selected by location, connections, gene expression or combinations of these features, researchers now have an unprecedented way to investigate the brain within living animals.
Modern experiments range from implanted fiber optics to three-dimensional holographic illumination of defined neuronal ensembles and noninvasive wearable LEDs, with interventions that can run from milliseconds to chronic use and effect sizes that change rapidly with changes in light intensity.
In humans, the loss of thymic function through thymectomy, environmental challenges, or age-dependent involution is associated with increased mortality, inflammaging, and higher risk of cancer and autoimmune disease (1). This is largely due to a decline in the intrathymic naïve T cell pool, whose generation is orchestrated by the thymic stroma, particularly thymic epithelial cells (TECs) (2). Upon challenges that affect the TEC compartment, the thymus is capable of triggering an endogenous regenerative response by engaging resident epithelial progenitors with stem cell features (3–5). Yet, after age-related atrophy or thymectomy resulting from myasthenia gravis or tumor removal (1), this regenerative response is unable to overcome the loss of thymic tissue, highlighting the need for therapeutic interventions.
The restoration of thymic functionality has been achieved to a limited extent via strategies targeting the thymic epithelial microenvironment or hematopoietic progenitors, modulating hormones and metabolism, or through cellular therapies and bioengineering (6). In mice, the up-regulation of Foxn1, a key transcription factor for thymus development and organogenesis (7), either directly or via its upstream effector bone morphogenetic protein 4 (BMP4), can support activity of cortical TECs (cTECs) (8, 9). Further, a combination of growth hormone and metformin has been shown to restore thymic functional mass in humans (10). Nevertheless, such strategies only lead to delayed thymic involution, and examples of complete thymus regeneration have not yet been described among vertebrates.
Because of its remarkable regenerative abilities that extend to parts of the brain, eye, heart, and spinal cord, and even entire limbs, the axolotl (Ambystoma mexicanum) is a powerful model for regeneration studies (11). The axolotl has offered insights into the mechanisms of positional identity (12), cell plasticity (13, 14), and the molecular basis of complex regeneration (15–18). The regeneration of axolotl body parts relies on remnants of the missing structure, with the exception of lens tissue, which can regrow from dorsal pigmented epithelial cells during a short window during development (19). However, whether de novo regeneration can occur for an entire complex organ, in axolotls or any other vertebrate, is unknown.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive upper and lower motor neuron (MN) degeneration with unclear pathology. The worldwide prevalence of ALS is approximately 4.42 per 100,000 populations, and death occurs within 3–5 years after diagnosis. However, no effective therapeutic modality for ALS is currently available. In recent years, cellular therapy has shown considerable therapeutic potential because it exerts immunomodulatory effects and protects the MN circuit. However, the safety and efficacy of cellular therapy in ALS are still under debate. In this review, we summarize the current progress in cellular therapy for ALS. The underlying mechanism, current clinical trials, and the pros and cons of cellular therapy using different types of cell are discussed. In addition, clinical studies of mesenchymal stem cells (MSCs) in ALS are highlighted. The summarized findings of this review can facilitate the future clinical application of precision medicine using cellular therapy in ALS.
ALS is believed to result from a combination of genetic and environmental factors (Masrori and Van Damme 2020). ALS exists in two forms: familial ALS (fALS) and sporadic ALS (sALS). fALS exhibits a Mendelian pattern of inheritance and accounts for 5–10% of all cases. The remaining 90–95% of cases that do not have an apparent genetic link are classified as sALS (Kiernan et al., 2011). At the genetic level, more than 20 genes have been identified. Among them, chromosome 9 open reading frame 72 (C9ORF72), fused in sarcoma (FUS), TAR DNA binding protein (TARDBP), and superoxide dismutase 1 (SOD1) genes have been identified as the most common causative genes (Riancho et al., 2019). Beyond genetic factors, the diverse pathological mechanisms of ALS-associated neurodegeneration have been discussed (van Es et al., 2017). The clinical symptoms of ALS are heterogeneous, with main symptoms including limb weakness, muscle atrophy, and fasciculations involving both upper and lower MNs.
A new University of California San Diego School of Medicine study offers a unified biological model to explain how genetic predispositions and environmental exposures converge to cause autism spectrum disorder (ASD).
The study, published in Mitochondrion, describes a “three-hit” metabolic signaling model that reframes autism as a treatable disorder of cellular communication and energy metabolism. The model also suggests that as many as half of all autism cases might be prevented or reduced with prenatal and early-life interventions.
“Our findings suggest that autism is not the inevitable result of any one gene or exposure, but the outcome of a series of biological interactions, many of which can be modified,” said study author Robert K. Naviaux, M.D., Ph.D., professor of medicine, pediatrics and pathology at UC San Diego School of Medicine.
Teenagers who are unhappy with their bodies are more likely to develop symptoms of eating disorders and depression in early adulthood, according to a new study led by University College London (UCL) researchers.
The research, believed to be the first of its kind, followed more than 2,000 twins born in England and Wales. It found that higher body dissatisfaction at age 16 predicted greater symptoms of eating disorders and depression well into the twenties, even after taking into account family background and genetics.
Researchers say the findings strengthen evidence that a negative body image is not just a reflection of poor mental health, but that it can also contribute to it.
An international collective of researchers is delivering new insights into why having multiple psychiatric disorders is the norm rather than the exception. In a study published today in the journal Nature, the team provides the largest and most detailed analysis to date on the genetic roots shared among 14 conditions.
The study is the latest effort from the Psychiatric Genomics Consortium’s Cross-Disorder Working Group, co-chaired by Kenneth Kendler, M.D., a professor in the Department of Psychiatry at Virginia Commonwealth University’s School of Medicine, and Jordan Smoller, M.D., a professor in the Department of Psychiatry at Harvard Medical School.
The majority of people diagnosed with a psychiatric disorder will ultimately be diagnosed with a second or third disorder in their lifetime, creating challenges for defining and treating these conditions. While a person’s environment and lived experience influence their risk for developing multiple disorders, their genetic makeup can also play a significant role.
Structural insights into PRC2 function in development and disease.
Polycomb repressive complex 2 (PRC2) is a central epigenetic regulator of developmental gene repression that displays remarkable complexity arising from multiple molecular layers.
Enzyme catalysis and chromatin targeting form the basis of the common and distinct functions of PRC2.1 and PRC2.2, serving as focal points in the cellular regulation of PRC2 activity under both physiological and pathological contexts.
Structural biology has begun to clarify the molecular mechanisms underlying key functions of PRC2 and uncover new modes of regulation, with much still remaining to be understood about the elaborate system of PRC2-mediated gene control. https://sciencemission.com/PRC2-function-in-development-and-disease
Polycomb repressive complex 2 (PRC2) is a key epigenetic enzyme complex that mediates developmental gene repression mainly by depositing the repressive H3K27me3 histone mark. PRC2 operates through its distinct forms, PRC2.1 and PRC2.2, each defined by unique accessory subunits, with additional complexity introduced by other molecular variants such as developmentally regulated homologs and isoforms. PRC2 function is primarily dictated by its enzymatic activity and chromatin recruitment, both of which are rigorously controlled during development and can be dysregulated by disease-associated mutations and oncoproteins. Structural biology has begun to provide important mechanistic insights into various aspects of PRC2 assembly, catalysis, chromatin targeting, and cellular regulation at atomic resolution, addressing several longstanding questions about the Polycomb repression system.
An international research team has identified a human protein, ANKLE1, as the first DNA-cutting enzyme (nuclease) in mammals capable of detecting and responding to physical tension in DNA. This “tension-sensing” mechanism plays a vital role in maintaining genetic integrity during cell division—a process that, when disrupted, can lead to cancer and other serious diseases.
The study, titled “ANKLE1 processes chromatin bridges by cleaving mechanically stressed DNA,” published in Nature Communications, represents a major advance in the understanding of cellular DNA protection.
The research was conducted through a cross-disciplinary collaboration between Professor Gary Ying Wai Chan’s laboratory at the School of Biological Sciences, The University of Hong Kong (HKU) and Dr. Artem Efremov’s biophysics team at Shenzhen Bay Laboratory (SZBL), with additional contributions from researchers at the Hong Kong University of Science and Technology (HKUST) and the Francis Crick Institute in London.